Project Summary Antibodies produced by activated B cells are a key element of a protective immune response against a number of pathogens. Yet, the host sacrifices normal production of B cells in the bone marrow during acute infections in favor of myelopoiesis. To compensate for this change in hematopoiesis the spleen can support myelopoiesis and erythropoiesis as part of a process known as extramedullary hematopoiesis, but whether it can support lymphopoiesis is unknown. The preliminary data shown here indicates that the spleen can serve as an alternative site for the production of B cells during an active infection. A lymphoid progenitor cell population with a lineage-Sca-1+c-kit- (LSK-) phenotype in mice expands and differentiates into B cells in response to a number of infections, including Plasmodium, and murine gammaherpesvirus-68 (MHV68). The B cells derived from these lymphoid progenitor cells not only maintain B cell numbers after infection, but also participate in the ongoing immune response through the production of antigen-specific antibodies. However, the events that lead to the activation and expansion of this cell population have not been defined, nor is it clear that these cells contribute toward long-term protection of the host. Our preliminary data indicate that LSK- cells utilize a different route for B cell development in the spleen than common lymphoid progenitor cells in the bone marrow. Building upon this preliminary data the work described in this proposal will address these knowledge gaps by (AIM 1) determining the contribution of LSK- derived B cells to host protection against Plasmodium yoelii and MHV68 infection, and (AIM 2) identifying the mechanisms that control differentiation of LSK- cells into B cells. To accomplish these goals we will utilize innovative state-of-the-art molecular and cellular immunological techniques. These approaches will provide valuable insight into our understanding of how LSK- cells contribute to humoral immunity after resolution of acute infection and identify key components involved in this process.